HER2, Tissue Factor, TROP2 and NECTIN4 as targets for antibody-drug conjugate (ADC) therapy in cervical cancer

Abstract

Early-stage cervical cancers are generally associated with good prognosis. However, for late stage or recurrent disease, survival rates drop significantly, with limited treatment options available. Antibody drug conjugates (ADCs) represent an emerging group of personalized drugs with promising response rates across multiple cancer types. Tisotumab vedotin (TV) is the only ADC approved by the Food and Drug Administration (FDA) for treatment of cervical cancers. No ADCs are approved for treatment of cervical cancers in Norway. The objective of this study was to characterize expression patterns of the ADC target proteins HER2, Tissue factor (TF), TROP2 and NECTIN4 in a large population-based cohort of cervical cancer patients, and to characterize ADC-protein expressing patients to gain knowledge on potential responders for ADC treatment.

Membrane expression of HER2, TF, TROP2 and NECTIN4 was assessed by immunohistochemistry (IHC) in a large prospectively collected population-based cohort of cervical cancer patients (n=532). Protein expression was scored according to the ASCO/CAP criteria applied for HER2 detection in breast cancer. Expression data was analyzed to detect correlations with clinicopathological characteristics through statistical analysis (e.g., chi-square test, Fisher's exact test, Mann-Whitney U test, Kruskal-Wallis test). Kaplan-Meier analysis was utilized to assess the prognostic value of protein expression.

All ADC targets showed tumor-specific membrane expression. Across three different HER2 antibodies, staining patterns were discordant with overexpression of HER2 in 20%, 12% and 8% of tumors in Series 1, -2 and -3, respectively. High membrane expression (≥2+) of TROP2 was observed in 68% of the primary tumors, and 68% of the recurrent lesions. High TF expression was observed in 48% of the primary tumors and in 43% of the recurrent lesions, while high expression of NECTIN4 was observed in 12% of the primary tumors and in 38% of the recurrent lesions. Overall, 80% of all tumors in this cohort expressed high (≥2+) levels of one or more of these ADC targets.

In conclusion, TF, TROP2 and NECTIN4 were highly expressed in primary and recurrent cervical cancer. Association with clinicopathological variables and survival was influenced by IHC method and antibody for HER2. Clinical trials evaluating the safety and efficacy of ADCs targeting the proteins evaluated in this study are highly relevant in cervical cancer. Further optimization of guidelines to improve protocols for detecting responders within subgroups of cervical cancer is highly warranted.